A balanced redox state is of utmost importance for processes that require precise cascades of regulatory pathways such as transmitter activity, receptor sensitivity, contractility on the organ level and development and adaptation on an organism level. During evolution organisms have developed mechanisms to use reactive oxygen species (ROS) as oxidation/reduction switches for the regulation of gene expression and enzymatic activities that are important components for the maintenance of homeostasis. ROS levels are balanced via their production and the activity of the antioxidant defence system (ADS) both dynamically interacting with metabolic regulation of homeostasis.
The aim of the project is to further explore the mechanisms of redox signalling mediated by ROS and the ADS. The occurrence of diapause in insects, and other forms of dormancy, has widely been documented but the exact cascade of the cellular events is not fully understood. The objective of this part of the research project is to contribute to the better understanding of the redox state in physiological adaptation such as the insect diapause, cold hardiness and resistance to desiccation as a survival strategy. Understanding such phenomena could be useful to establish novel methods for cell and tissue preservation. The accumulation of glycerol associated with cold hardiness in the Corn borer Ostrinia nubilalis and the unique ability of Arctic springtail Megaphorura arctica, formerly Onychiurs arcticus to survive in an almost dehydrated state, producing trehalose as water exchange will be further explored by our group. The analysis of ROS and ADS in the context of production of glycerol as cryo/anhydro protectants in Ostrinia nubilalis will serve to determine the role of redox regulation in mediating processes that enable survival under the such unfavorable conditions. Genomic studies and micro array analyses of Megaphorura arctica have identified a number of genes and cellular processes that could be a part of the regulatory processes that are crucial for the cryoprotective dehydration of these species. Genes encoding for antioxidants have been identified. It appears that the oxidative stress response is important, not only in the prevention of the oxidative cell damage caused by water loss, also in the maintenance of intracellular redox homeostasis, important for metabolic adjustments during dehydration and trehalose synthesis. Since one of the most important functions of ROS is to be part of intracellular signalling pathways our proposed studies will provide new insights into the underlying biochemical mechanisms of adaptive strategies such as the resistance to desiccation and low temperatures.
At the molecular level ROS also influence homeostatic function by redox modification of cellular transmitter receptors. In order to better understand and deal with problems of irregular smooth muscle contractile activity it is important to uncover aspects of ROS and ADS driven physiological pathways during contraction. This will lead to new scientific approaches to manage dysfunctional contractions possibly by limiting ROS production through stimulation of enzymatic or non-enzymatic antioxidative pathways through which these ROS operate. Our previous results showed that exogenous hydrogen peroxide causes relaxation of smooth muscle via voltage-dependent potassium channels. This could represent the main mechanism for hydrogen peroxide-induced relaxation. We will examine the effect of different reductive agents on isolated smooth muscles and data will be used for interpretations of some pathological processes. Pertinent to this we will investigate redox processes in the uterus, as well as specific interactions between the uterus and placenta/fetus in different pathophysiological pregnancies, that may be related to misbalanced generation of ROS. Accumulating evidence points to many interrelated mechanisms that increase production of ROS and/or decrease antioxidant protection in schizophrenic patients. Therefore, oxidative stress may have a pathophysiological role in all the subtypes of schizophrenia. Evidence of excessive ROS generation in schizophrenia is premised on the assumption that there is increased catecholamine turnover and that high levels of lipid peroxidation product have been noticed in plasma and cerebrospinal fluid of schizophrenics. Antioxidant defence enzymes have also been found to be altered in erythrocytes of schizophrenics. The effect of drugs used in schizophrenia treatment on lipid metabolism and ROS and in vitro examination of the mechanism of action of new drugs such as tianeptine through its effects on isolated smooth muscles will be examined. Our hypothesis is that patients with various forms of brain tumors also have oxidative stress which is reflected in the circulation. The determination of ADS enzyme activity and correlation analysis both in tumor tissue and in blood of the same patients will provide relevant information to identify the main ROS which induce these changes.
Malignant pleural mesothelioma (MPM) is an aggressive tumour resistant to most anticancer therapies. The etiopathogenesis of MPM is significantly associated with exposure to asbestos fibres and to carbon nano-tubes in the human environment. The generation of oxidants by fibres induces DNA and chromosome damage linked to oxidative stress following phagocytosis. The generation of oxidants by fibres of particles therefore results in cell injury and activation of different signalling pathways. The balance of oxidant-antioxidant pathways is crucial as disturbances in this equlibrium reduce the capacity of the cells to protect themselves against free radicals, in other word, their ability to produce sufficient antioxidant enzymes.
From: 20.01.2001. To: 20.12.2031.
►Institute for Biological Research "Siniša Stanković", University of Belgrade
►School of Medicine, University of Belgrade
►Faculty of Sciences, University of Novi Sad
►Faculty of Biology, University of Belgrade
|Dr Duško Blagojević, research professor||Institute for Biological Research "Siniša Stanković", University of Belgrade|
|Dr Ivan Spasojević, research professor||IMSI, University of Belgrade|